Human parainfluenza viruses (HPIVs) are members of the Paramyxovirinae subfamily of the Paramyxoviridae family of viruses. Paramyxoviruses are enveloped viruses that replicate in the cytoplasm and bud at the plasma membrane and have a single-stranded negative-sense non-segmented RNA genome of approximately 13-19 kb. HPIVs are important pathogens in human populations, causing severe lower respiratory tract infections in infants and young children. Human parainfluenza virus type 1 (HPIV1) and type 2 (HPIV2) are the principal etiologic agents of laryngotracheobronchitis (croup) and also cause pneumonia and bronchitis (Chanock et al., 2001, Parainfluenza Viruses 4th Ed., Knipe et al. eds., Lippincott (Philadelphia, Pa.) 1341-1379). Human parainfluenza virus type 3 (HPIV3) is a leading cause of hospitalization for viral lower respiratory tract disease in infants and young children (Chanock et al., 2001, supra). HPIVs are also important causes of respiratory tract disease in adults. Collectively, HPIV1, HPIV2, and HPIV3 have been identified as the etiologic agents responsible for approximately 18% of hospitalizations for pediatric respiratory disease (Murphy et al., 1988, Virus Res., 11:1-15). HPIVs have also been implicated in a significant proportion of cases of virally induced middle ear effusions in children with otitis media (Heikkinen et al., 1999, N. Engl. J. Med., 340:260-264).
Despite considerable efforts, there are currently no parainfluenza virus vaccines available. Attenuated paramyxoviruses suitable for use in vaccines are currently under development. Two live attenuated HPIV3 vaccine candidates, a temperature sensitive (ts) derivative of the wild type HPIV3 JS strain and a bovine PIV3 strain, are currently being tested. (Karron et al, Pediatric Infectious Dis. J., 15:650, 1996; Karron et al, J. Infect. Dis., 171:1107, 1995; Karyon et al., J. Infect. Dis., 172:1445, 1995). A chimeric PIV1 vaccine candidate has been generated by replacing the PIV3 HN and F open reading frames with those of PIV1 in a PIV3 full length cDNA (Tao et al., 2000a). A chimeric HPIV3 bearing the glycoproteins of HPIV2 was also generated previously (Tao et al., 2000b). Attenuated HPIV2 strains have previously been made by introducing mutations into the L protein (WO 04/027037). Recombinant viruses include HPIV3 recombinant viruses having three identified mutations in the L gene. (Skiadopoulos et al, J. Virol. 72:1762, 1998; Tao et al, J. Virol. 72:2955, 1998; Tao et al, Vaccine, 17:1100, 1999). These live attenuated vaccine candidates can induce protection against HPIV infection in some experimental animal models. (Karyon et al, J. Infect. Dis., 172:1445, 1995b; Skiadopoulos et al, Vaccine 18:503, 1999; Skiadopoulos, Virology, 297: 136, 2002). However immunity to previous HPIV3 infection could limit the use of chimeric HPIV3 vaccines bearing heterologous HPIV1 or HPIV2 glycoproteins. Strategies to develop live viral vaccines are important in the design of safe and stable viral vaccine candidates.
In addition to providing possible vaccine candidates for protection against parainfluenza virus infection and disease, candidate vaccines may also be useful in expressing heterologous antigens. Studies demonstrate that foreign genes may be inserted into a paramyxovirus genome and are well expressed. (Bukereyev et al, J. Virol., 70:6634, 1996; Hassan et al, Virology, 237:249, 1997; Jin et al, Virology 251:206, 1998; Schmidt et al., 2001; Skiadopoulos et al., 2002). However, in order to develop vectors for vaccine use, more than a high level of protein expression is required. Factors in the design of a vector for delivery of heterologous antigens include viral host range, immunogenicity, and pathogenicity. Some negative strand viruses are undesirable as vectors because of their pathogenicity, such as measles and rabies virus.
Thus, there remains a need to develop effective immunogenic compositions to alleviate health problems associated with HPIV viruses and other pathogens, and to immunize against multiple HPIV serotypes. There is also a need to develop immunogenic compositions to deliver heterologous antigens.